More that 90% of cancer-related deaths are caused by dissemination of cancer cells to distant organs with subsequent formation of secondary tumours. In contrast to the primary tumour, metastasis is largely incurable because of its systemic nature and its frequent association with resistance to existing therapeutic agents. The better understanding of the mechanisms of metastatic spread of cancer cells and the pathways involved in this process had identified new targets and opened new possibilities to treat cancer. Dissemination of cancer cells in the body inevitably occurs via interaction with the surrounding “normal” cells, collectively called cancer-associated stroma (Langley & Fidler, 2011). This means that the search for potential therapeutic targets for anti-metastatic therapy has considered both tumour- and stroma-cell derived molecules.
Among potentially applicable anti-metastatic targets, the protein S100A4 has been suggested as a therapeutic intervention site to prevent metastasis. S100A4 belongs to the S100 family of small Ca-binding proteins with diverse extra- and intra-cellular function (Donato, 2003). Numerous studies connect the S100A4 activity with tumour progression and metastasis formation. This evidence has been accumulated using in vitro studies of cancer cell lines, transgenic and knockout mouse models and assessment of its prognostic significance for metastasis in patients with cancer (Boye et al., 2010; Helfman et al, 2005; Mishra et al., 2011). The S100A4 activity is associated with stimulation of cancer cell motility and invasion, normal and aberrant proliferation, apoptosis and differentiation. It is involved in signaling pathways leading to the remodeling of the cell membrane and the extracellular matrix; modulation of cytoskeletal dynamics, acquisition of invasiveness and induction of angiogenesis (Sherbet, 2009). It has been shown that S100A4 is expressed in certain tumour cells, but more generally it is activated and secreted from certain cancer-associated stroma cells which lead to its accumulation in the tumour microenvironment. Moreover, it has been shown that metastatic microenvironment contains greater numbers of S100A4-positive stromal cells than the primary tumour microenvironment (Cabezón et al., 2007; Grum-Schwensen et al., 2005; 2010; Maelandsmo et al., 2009; Schmidt-Hansen, et al., 2004a).
Furthermore, S100A4 has been shown to maintain the stemness properties and tumourigenicity of cancer-initiating cells in head and neck cancers (Lo et al., 2011).
WO 2011/157724 (Lykera Biomed SA) describes anti-S100A4 antibodies that have anti-angiogenic activity and which bind an epitope comprising the amino acid sequence ELPSFLGKRT (SEQ ID NO: 16) or EGFPDKQPRKK (SEQ ID NO: 17).
However, while the role of S100A4 in tumour progression and metastasis formation has been studied, it remains the case that anti-metastatic therapy is in a rudimentary state largely unmet by existing therapies.